The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure.
The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure.
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DOI：
10.1016/j.molcel.2017.07.027
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发表时间：
2017-09-21
期刊：
影响因子：
16
通讯作者：
Schimenti JC
中科院分区：
文献类型：
--
作者：
Rinaldi VD;Bolcun-Filas E;Kogo H;Kurahashi H;Schimenti JC
减数分裂期间同源染色体的配对和联会对于产生遗传上正常的配子至关重要，并且依赖于通过同源重组修复SPO 11诱导的双链断裂（DSB）。为了防止遗传缺陷的传播，不同的生物体已经进化出消除含有未修复的DSB或未突触染色体的性母细胞的机制。在这里，我们表明，CHK 2（CHEK 2）依赖的DNA损伤检查点剔除不仅重组缺陷的小鼠卵母细胞，但也SPO 11缺陷的卵母细胞是严重缺陷的同源突触。检查点在那些在后期前期I中积累阈值水平自发DSB（~10）的卵母细胞中被触发，其修复被未突触染色体轴上HORMAD 1/2的存在抑制。此外，Hormad 2缺失挽救了卵母细胞的生育力，这些卵母细胞含有从突触染色体中去除HORMAD所需的基因（Trip 13）中的突触熟练的DSB修复缺陷突变，这表明小鼠中许多减数分裂DSB通常通过姐妹间重组修复。
Pairing and synapsis of homologous chromosomes during meiosis is crucial for producing genetically normal gametes, and is dependent upon repair of SPO11-induced double stranded breaks (DSBs) by homologous recombination. To prevent transmission of genetic defects, diverse organisms have evolved mechanisms to eliminate meiocytes containing unrepaired DSBs or unsynapsed chromosomes. Here, we show that the CHK2 (CHEK2)-dependent DNA damage checkpoint culls not only recombination-defective mouse oocytes, but also SPO11-deficient oocytes that are severely defective in homolog synapsis. The checkpoint is triggered in those oocytes that accumulate a threshold level spontaneous DSBs (~10) in late Prophase I, the repair of which is inhibited by presence of HORMAD1/2 on unsynapsed chromosome axes. Furthermore, Hormad2 deletion rescued fertility of oocytes containing a synapsis-proficient, DSB repair-defective mutation in a gene (Trip13) required for removal of HORMADs from synapsed chromosomes, suggesting that many meiotic DSBs are normally repaired by intersister recombination in mice.
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